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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Investigating the role of inheritance in drug induced hepatotoxicity

Daniel K. Burns, PhDSenior Vice President,GlaxoSmithKline Research and DevelopmentInvestigating the role of inheritance in drug induced hepatotoxicity [PDF]

Hepatotoxicity is one of the leading causes of attrition of compounds in clinical development. Advances in animal models and in vitro assays have been useful in identifying compounds with generalized liver toxicity. However, rare liver toxicities continue to be seen in clinical trials and in post marketed therapeutics. These adverse events have serious implications for the pharmaceutical industry, academic investigators, regulatory authorities and most importantly patients. The challenge is to identify those individuals who are at risk for the rare or idiosyncratic hepatotoxicity events prior to compound exposure or before they experience serious injury. The availability of the human genome sequence and mapped high density genetic markers affords an opportunity to investigate the role of inheritance in susceptibility to drug induced liver injury. GlaxoSmithKline has experience in performing high density genome wide association scans to identify genetic factors that contribute to rare adverse events. A potential collaboration to perform a high density scan on subjects recruited in the DILIN will be discussed. GSK would undertake genotyping at 500,000+ markers per subject and make this data available to the DILIN Principal Investigators, participate in genetic analysis and make data and results available in the public domain. The genetic data will serve as a resource to evaluate future hypotheses and can be used to guide further physiological investigations to elucidate the biochemical basis of this phenomenon and potential novel biomarkers. It is important to bring state of the art genome techniques to understand genetic contributions to this serious, poorly understood phenomenon to improve drug discovery and development and enhance patient care.

Biographical Sketch

Dan was educated at Indiana University receiving a Bachelor of Science in 1977, a Masters degree in 1979 and a Ph.D. in Cellular, Molecular and Developmental Biology in 1984. He pursued post doctoral research at Hoffmann-La Roche in Nutley New Jersey, utilizing molecular biology techniques to investigate the structure function relationship of proteins. He subsequently assumed a staff scientist position at Hoffmann La Roche and established a laboratory group investigating the molecular basis of the inflammatory response. In 1993 Dan joined Glaxo to establish a molecular biology laboratory to investigate the molecular and genetic basis of insulin resistance and type II diabetes. Following the merger of Glaxo and Burroughs Wellcome he assumed leadership responsibilities for the Genetics Research Initiative in Diabetes, participated in the development of the Genetics Directorate and served as the Head, Department for Human Genetics. As head of GSK’s Discovery Genetics, he directed the activities of 140 scientists in the U.S. and U.K. aimed at identifying disease susceptibility genes, determining the function of genes and understanding the role of genetics in the safety and efficacy of medicines. He now serves as Senior VP of the GR-Therapeutic Area Teams (TATs), which are responsible for interfacing with all of R&D and determining how genetics and genomics can best support drug discovery and development and optimize the delivery of safe and effective medicines to the people who need them.